Neuropathology, Genetics & Biomarker Core D Core Leader: John Q. Trojanowski, Core Co-Leader: Eddie Lee, Co-Investigator: Vivianna Van Deerlin Summary/Abstract: Neuropathology, Genetics & Biomarker Core D Nearly all neurodegenerative disorders are characterized by progressive accumulations of pathological deposits of disease protein aggregates within cells, blood vessels or in the neuropil and these deposits are the signature CNS lesions that define these disorders as exemplified by the senile plaques and neurofibrillary tangles required for the postmortem diagnosis of Alzheimer's disease (AD). However, Lewy bodies (LBs) and TDP-43 inclusions occur in >50% of AD patients, and mixed pathologies including hippocampal sclerosis and cerebrovascular disease are features of AD including prodromal stages of disease as in mild cognitive impairment (MCI) which shows AD and additional pathologies associated with other forms of dementia at autopsy. Further, 20-30% of patients with clinical AD have another neurodegenerative dementia other than AD and a similar percentage of patients diagnosed with clinical frontotemporal degeneration (FTD) have AD pathology while the remaining patients have autopsy confirmed frontotemporal lobar degeneration (FTLD) with tau, TDP-43 or FUS aggregates. Thus, a definite diagnosis of AD or related dementias is established only by postmortem neuropathology studies as performed in Core D, and an accurate neuropathology diagnosis is essential to elucidate mechanisms of AD and related dementias. Since multiple genetic factors contribute to the risk for AD and biomarkers signal disease onset/progression, DNA and biofluids are critical for clinical genetic and biomarker studies of AD. Hence, the University of Pennsylvania (Penn) AD Core Center (ADCC) collects, characterizes and banks CNS tissues, DNA and biofluids from well-characterized patients with MCI, AD and related disorders as well as normal controls followed in Clinical Core B. This approach enables a more comprehensive understanding of an individual patient's genetic risks, clinical manifestations, disease progression and neuropathology which are essential for conducting ADCC related research using Penn ADCC resources. Accordingly, Core D is the ?Neuropathology, Genetics and Biomarker Core? of this ADCC and it supports the mission of the Penn ADCC by working seamlessly with all Cores to accomplish its goals.